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doi: 10.1093/pch/pxy093
Position Statement
Position Statement
Abstract
Global developmental delay (GDD) and intellectual disability (ID) are common concerns in the paediat-
ric setting. Etiologies of both conditions are highly heterogeneous. The American Academy of Pediatrics,
the American Academy of Neurology and the British Columbia-based Treatable Intellectual Disability
Endeavor (TIDE) protocol have each proposed multitiered investigations of GDD/ID to guide phy-
sicians toward an understanding of etiology that optimizes therapeutic yield. This statement provides
a framework for the clinical investigation of GDD/ID in children, along with an updated protocol for
Canadian physicians to follow in the etiological investigation of GDD/ID. The revised protocol is based
on current knowledge and existing guidelines. Key elements of investigation include formal vision and
hearing testing, chromosomal microarray, Fragile-X DNA testing and first-tier testing for treatable inborn
errors of metabolism. Brain imaging is recommended in the presence of specific neurological findings.
Each algorithm was developed to screen for the most com- History and physical examination
mon or treatable etiologies first. By contrast, other pathways In one recent review, an etiological diagnosis based on history
propose an approach based on checklists and likelihood ratio and physical examination was found in 12.5% to 38.6% of cases
models, stopping investigation when the clinician feels that it (3), confirming that these steps mark the most important phase
would not alter outcome, even without a diagnosis (3). One of investigation (2,3,7,8). A three-generation family history, a
important ‘clinical pearl’ is to look for clinical characteristics psychosocial history, detailed prenatal and birth histories and
pointing toward a specific etiology and order testing for that the timing of major milestones should be recorded as accu-
diagnosis first. When no apparent cause can be identified, a rately as possible (Table 3). A neurodevelopmental assessment,
stepwise approach—conducted in collaboration with a genet- including current developmental level and a systematic physi-
icist—is recommended, with paediatricians leading the investi- cal examination (Table 3) can either point toward a specific
gation whenever possible. See Figure 1 for a suggested approach diagnosis or guide laboratory testing. When a specific etiology
to testing. is suspected at that point or when a family history of disorder
Diagnosis No
established?
Yes
Yes Diagnosis
established?
• Family counselling
• Referral as needed No
• Brain MRI
• Consult
Genecs/Metabolics for:
• Further metabolic tesng
(Tier 2 of TIDE protocol)
• Gene Panels (e.g., XLID,
Re Syndrome variants)
• Consider neurology referral
Yes
Diagnosis
established?
No
Periodic reevaluaon
Figure 1. Algorithm for investigating global developmental delay or intellectual disability. Figure available in colour online.
EEG Electroencephalogram; GDD Global developmental delay; ID Intellectual disability; MRI magnetic resonance imaging; XLID X-linked intellectual disability
associated with GDD/ID has been established, specific testing AAP, the AAN, the International Standard Cytogenetic Array
for this disorder should be ordered first (Figure 1). and the American College of Medical Genetics (2,4,9,10). It
is the single test with the best diagnostic yield (7,8) (at 8% to
Sensory evaluation 20%), exceeded in efficacy only by clinical evaluation from an
According to the AAN (4) and other reviews (5,7,9), chil- experienced clinician specializing in GDD/ID (2,4,11). The
dren with GDD/ID should be referred for a formal assessment variation in yield reported in different studies can be explained
of their vision (optometry or ophthalmology) and hearing. by the absence of stratification for severity and the presence
Identifying a sight or hearing deficit can alter management of other anomalies. Therefore, it remains uncertain whether
course and guide further investigation. CMA is useful in mild (according to DSM-5) familial ID.
Those patients could simply represent the lower percentiles
Genetic testing of the IQ Gauss curve and the etiologies are often multifac-
Chromosome microarray torial. When multiple congenital anomalies are present, the
The use of chromosome microarray (CMA, also referred to American College of Medical Genetics still recommends CMA
as comparative genomic hybridization or CGH) as a first-line as a first-line investigation, unless a specific diagnosis is being
investigation in children with GDD/ID, is endorsed by the considered (10).
• Family history of IEM or developmental disorder or unexplained neonatal or sudden infant death
• Consanguinity
• Intrauterine growth retardation
• Failure to thrive
• Head circumference or stature growth abnormality (>2 SD above or under the mean)
• Recurrent episodes of vomiting, ataxia, seizures, lethargy, coma
• H
istory of being severely symptomatic and needing longer to recover with benign illnesses (e.g., upper respiratory tract
infection)
• Unusual dietary preferences (e.g., protein or carbohydrate aversion)
• Regression in developmental milestones
• Behavioural or psychiatric problems (e.g., psychosis at a young age)
• Movement disorder (e.g., dystonia)
• Facial dysmorphism (e.g., coarse facial features)
• Organomegaly
• Severe hypotonia
• Congenital nonfacial anomalies
• Sensory deficits, especially if progressive (e.g., cataracts, retinopathy)
• Noncongenital progressive spine deformities
• Neuro-imaging abnormalities
among provinces/territories. Even with an effective screening two-tiered algorithm. Tier 1 comprises a group of tests capa-
program, some IEMs are easy to miss (2,5). ble of identifying at least three IEMs, along with being readily
While rapid access to a clinical geneticist or metabolic special- accessible, minimally invasive and economical (in Vancouver,
ist for an evaluation identifying the most probable IEM would the whole test group costs about $528).
be ideal, it is not a reality in most of Canada. Also striking is that First-tier tests can identify 60% of currently known treat-
as much as two-thirds of children with GDD/ID have no recog- able IEMs causing ID. TreatableID.org is a web app (www.
nizable pattern of symptoms pointing toward a specific diagno- treatable-id.org) containing an algorithm that is regularly
sis. Nonspecificity often precludes the timely identification of a updated and describes 81 treatable IDs by their biochemi-
potentially treatable disorder, especially in late-onset disorders cal defects, diagnostic tests, clinical features and treatment
or in milder cases, where complete symptomatology has not modalities (17). The algorithm developers recommend tier-1
developed. The typical metabolic workup (lactate, ammonia, testing before genetic testing and neuroimaging, emphasizing
chromatography of plasma amino acids and urinary organic the treatable nature of the disorders included and the relative
acids) has a diagnostic yield of less than 1% to 5% (7), there- urgency to identify them. The AAP recommends considering
fore supporting testing only when clinical red flags are present. a metabolic workup at the same time or soon after CMA and
However, previous studies were designed to identify an etio- Fragile X DNA testing (2). Tier-1 content is the same for both
logical yield and ignored the ‘therapeutic yield’ (i.e., the iden- groups, except for the addition of copper and ceruloplasmin in
tification of a treatable disorder). Series with a more extended the TIDE protocol. The AAN adds basic metabolic tests that
metabolic workup revealed a yield of more than 5% (5). It is can guide further testing: blood sugar, blood gas, lactate and
also known that many treatable causes of GDD/ID do not pres- creatine kinase. Table 5 and Figure 1 summarize first-tier lab-
ent with developmental regression (5). One Canadian initiative oratory investigations that should be ordered for all patients
from the B.C. Children’s Hospital (5), based on a review of the whose GDD/ID presents without a recognizable constellation
literature (16,17) identifying 89 IEMs amenable to treatment of symptoms. An evaluation or a discussion with a metabolics
(17), aims to identify diseases before they become severe or specialist should be considered in the presence of red flags to
irremediable complications develop. This protocol proposes a tailor the laboratory investigation to that specific patient.
ALT Alanine aminotransferase; AST Aspartate aminotransferase; GDD Global developmental delay; ID Intellectual disability; TSH Thyroid-
stimulating hormone.
*Perform testing after 4 h to 8 h of fasting. **Recommended tier-1 test in the TIDE protocol, but not by AAP, AAN. Consider as a first-line inves-
tigation when hepatomegaly, dystonia, abnormal liver function findings are present. ***Clinical expert recommendation only. Consider biotinidase
testing when severe hypotonia, seizures are present.
ADDITIONAL INVESTIGATIONS when neurological findings are present (9). According to expert
opinion, a brain MRI with spectroscopy is indicated in all cases
Thyroid testing
of intractable epilepsy or developmental regression.
Hypothyroidism is a common, reversible cause of GDD/ID,
with an incidence of approximately 1 out of 3,500 live births.
Electroencephalogram
Many study authors recommend screening for thyroid func-
Uncontrolled epilepsy or epileptic syndromes, such as Landau-
tion (9), but the AAN states that the test does not need to be
Kleffner syndrome, can be associated with developmental delays
repeated when newborn screening is present (4). It is included
or regression. Seizures are a common symptom of IEMs. An elec-
in tier 1 (Table 5) whether or not newborn screening is per-
troencephalogram is justified when there is clinical suspicion of
formed, such that acquired cases and hypothyroidism cases of
seizures, speech regression or neurodegenerative disorder (9).
hypothalamic or pituitary origin are not missed.
recommended. If the diagnosis is not established, consider 4. American Academy of Neurology. Evaluation of the Child with Global
Developmental Delay. 2011. www.aan.com/guidelines (Accessed March 17, 2017).
consultation with genetics/metabolic specialist. 5. van Karnebeek CD, Stockler-Ipsiroglu S. Early identification of treatable inborn
• Chromosomal microarray and Fragile X DNA testing are first- errors of metabolism in children with intellectual disability: The Treatable
Intellectual Disability Endeavor protocol in British Columbia. Paediatr Child Health
line investigations for children with unexplained GDD/ID. 2014;19(9):469–71.
• Evidence supports Tier-1 (Table 5) testing for treatable 6. Shaffer LG; American College of Medical Genetics Professional Practice and
Guidelines Committee. American College of Medical Genetics guideline on the
inborn errors of metabolism (IEMs) in children with unex- cytogenetic evaluation of the individual with developmental delay or mental retar-
plained GDD/ID, even when clinical red flags are absent dation. Genet Med 2005;7(9):650–4.
and a normal newborn screen has been obtained. 7. Tirosh E, Jaffe M. Global developmental delay and mental retardation–A pediatric
perspective. Dev Disabil Res Rev 2011;17(2):85–92.
• Brain imaging is recommended as a first-line investigation 8. Wong VC, Chung B. Value of clinical assessment in the diagnostic evaluation of
for patients with microcephaly, macrocephaly, seizures or global developmental delay (GDD) using a likelihood ratio model. Brain Dev
2011;33(7):548–57.
abnormal neurological findings. For others, imaging may 9. Silove N, Collins F, Ellaway C. Update on the investigation of children with delayed
be postponed until first-line genetic and metabolic investi- development. J Paediatr Child Health 2013;49(7):519–25.
10. Manning M, Hudgins L; Professional Practice and Guidelines Committee, American College
gations have been performed. Consider the risks and ben- of Medical Genetics. Array-based Technology and Recommendations for Utilization in
efits of sedation in each case. Magnetic resonance imaging Medical Genetics Practice for Detection of Chromosomal Abnormalities. 2010. www.acmg.
net/StaticContent/PPG/Array_based_technology_and_recommendations_for.13.pdf
(MRI) is the modality of choice.
(Accessed March 17, 2017).
• Order lead level and iron studies for children at risk. 11. Sherr EH, Michelson DJ, Shevell MI, Moeschler JB, Gropman AL, Ashwal S.
• Whole-exome or -genome sequencing may be indicated in Neurodevelopmental disorders and genetic testing: current approaches and future
advances. Ann Neurol 2013;74(2):164–70.
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ily available global developmental delay or intellectual disability. Semin Pediatr Neurol
2012;19(4):173–80.
13. Hersh JH, Saul RA; Committee on Genetics. Health supervision for children with
Fragile X syndrome. Pediatrics 2011;127(5):994–1006.
Acknowledgements 14. Wright CF, McRae JF, Clayton S, et al. Making new genetic diagnoses with old data: itera-
tive reanalysis and reporting from genome-wide data in 1,133 families with developmental
This position statement has been reviewed by the Community disorders. Genet Med 2018.
Paediatrics Committee and the Early Years Task Force of the Canadian 15. Boycott K, Hartley T, Adam S, et al.; Canadian College of Medical Geneticists. The
Paediatric Society. clinical application of genome-wide sequencing for monogenic diseases in Canada:
Position statement of the Canadian College of Medical Geneticists. J Med Genet
2015;52(7):431–7.
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